Seventeen unrelated children have been studied with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive non-malignant lymphadenopathy, autoimmune phenomena and expanded populations of TCR/CD3+, CD4-, CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Nine children were found to have defective Fas-mediated T lymphocyte apoptosis, and in eight of these children a unique, deleterious mutation was found in the Fas gene. Two mutations produce early truncations in the extracellular domain of the protein; however, four others, with the remainder under study, had a dominant negative phenotype when co-expressed with normal Fas. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this newly recognized disorder of lymphocyte homeostasis and peripheral self-tolerance. Family studies demonstrated the inheritance of the mutant Fas alleles with a dominantly inherited cellular apoptosis defect. However, overt autoimmunity appears to require additional factors besides heterozygous Fas mutation. Further studies of family members revealed one extended family in which a dominant negative Fas mutation segregated with clinical abnormalities ranging from benign lymphadenopathy to autoimmune disease with elevated double negative T cells to Hodgkin's disease and non-Hodgkin's lymphoma. The possibility that Fas and other proteins which participate in lymphocyte apoptosis might function as oncogenes in the development of Hodgkin's disease is being pursued. In addition a transgenic mouse model of dominant negative Fas mutations is being developed. Constructs placing normal or mutant human Fas alleles under the control of the pim1 promoter has been used to generate transgenic mice in which expression studies are being undertaken.